The effects of intermittent fasting on human and animal

health a systematic review

Thesis January 2012, University of Lund by Bojan Kostevski
Center for Primary Health Care Research, Lund University, CRC, SE-205 02 MALM, Sweden
Supervised by: Bengt Zller, Staffan Lindeberg
Examination: Daniel Arvidsson
Keywords: intermittent fasting, calorie restriction, obesity, aging, cardiovascular health, glucose
metabolism, cancer, neurodegenerative disease.

Abstract
An increasing number of animal studies have shown altered markers for health in subjects exposed to
intermittent fasting, i.e. regularly and repeatedly abstaining from eating during 12-36 hours per period. It
has been hypothesized that the reported beneficial health effects from caloric restriction on excess body
weight, cardiovascular risk factors, glucose metabolism, tumor physiology, neurodegenerative pathology
and life span can be mimicked by alternating periods of short term fasting with periods of refeeding, without
deliberately altering the total caloric intake. Therefore, a systematic review of available intervention studies
on intermittent fasting and animal and human health was performed. In rodents, intermittent fasting
exhibits beneficial effects including decreased body weight, improved cardiovascular health and glucose
regulation, enhanced neuronal health, decreased cancer risk and increased life span some of the effects
independent of the effects attributed to calorie restriction alone. The human studies performed to date are
generally of low-quality design. Beneficial effects such as weight loss, reduced risk for cardiovascular disease
and improved insulin sensitivity have been observed, but conflicting data exists. The potential health
promoting effects of intermittent fasting in humans and applicability to modern lifestyle are discussed.

Introduction
Calorie restriction and intermittent fasting
Almost a century has passed since Osborne and colleagues in 1917 observed that reducing calorie
intake in rats increased the animals life span (1). In 1935, McCay et al. were first to describe that
calorie restriction deliberately reducing calories without causing malnutrition prolongs mean
and maximal lifespan in rats compared with rats fed ad libitum (2). Numerous subsequent studies
have confirmed that a calorie restriction of 30 to 60 percent of ad libitum intake increases the life
span by similar amounts in a range of organisms including yeast, roundworms and rodents, while
simultaneously decreasing or delaying the occurrence of age related diseases such as numerous
cancers (including lymphomas, breast and prostate cancers), hypertension, stroke, diabetes,
nephropathy, autoimmune disorders and other risks factors for cardiovascular disease (3,4).
Furthermore, it is suggested that calorie restriction can display beneficial effects in rodent models of
various neurodegenerative diseases such as Alzheimers, Parkinsons and Huntingtons disease (5).
Accordingly, overeating is considered a risk factor for the majority of the conditions mentioned
above, further supporting the hypothesis that calorie restriction can be beneficial (6,7). To further
explore the relevance of these findings in rodents on primate health, a study was initiated at the
Wisconsin National Primate Research Center (WNPRC) in 1989, studying a 30% calorie restriction
in rhesus monkeys (8). The incidence of diabetes, cancer, cardiovascular disease and brain atrophy

was reduced in animals on the calorie restricted diet compared with monkeys on the control diet.
Twenty years into the study, 80% of the calorie restricted animals were still alive, compared with
50% of the control fed animals. The data obtained to date suggest that calorie restriction slows aging
in primates and improves health.
Calorie restriction in humans is associated with weight loss, reduced inflammation and improved
markers for cardiovascular and metabolic health in obese{Formatting Citation} (9,10) as well as
non-obese (11,12) subjects, proposing a novel therapy for increasing life span. However, adherence
to the recommended calorie reduced/low fat diet remains an issue for some people in the long term
(13,14).
To improve compliance in human subjects, a model in which calories are periodically restricted has
been proposed. Intermittent fasting is a paradigm where periods of fasting are cycled with periods
of over-eating where subjects are fed ad libitum. Alternate-day fasting, one model of intermittent
fasting has been widely used in animal calorie restriction research because it has shown to result in
reduced food intake over time and decrease body weight in rats (15). In human trials, intermittent
fasting has been shown to be equally effective as daily calorie restriction for causing weight loss in
obese subjects (16).
While alternate-day fasting leads to calorie restriction over a two-day period in many rodent
species, in some strains of mice, the animals managed to compensate for the calorie deficit created
on fast days by increasing their intake on feast days twofold and thus keeping the total calorie intake
over a two day period at the same level as in mice fed an ad libitum diet (17). These mice managed to
maintain constant body weight but, interestingly, still acquired some of the health benefits as rats
on daily calorie restriction. This lead to the hypothesis that by implementing periods of fasting, one
could improve health without deliberately reducing calorie intake. My objective was to review
relevant intervention studies on the effects of intermittent fasting on energy balance, cardiovascular
risk factors, glucose metabolism, neurodegenerative pathology, tumor physiology and life span.
Significance: The study will be important for the understanding of excess caloric intake and the
management of obesity, and identify ways to alter cardiovascular, metabolic and neuronal health.

Methods
A systematic review of intervention studies in mammals, including humans was performed.
PubMed between 1973 and 2011 was searched by use of relevant MeSH terms related to the effects
of intermittent fasting on excess body weight, energy balance, aging physiology, cardiovascular risk
factors, glucose metabolism, tumor physiology and neurodegenerative pathology. For each of the
MeSH terms, the search process was restricted by use of non-MeSH terms such as intermittent
fasting, periodic fast, alternate-day fasting and other relevant terms. All terms used are listed in
Table 1. Furthermore, relevant review articles on calorie restriction and intermittent fasting were
reviewed for additional relevant studies to include in the review. Studies were included in the review
if short term fasting was the primary intervention and studied any of the above mentioned
outcomes. Studies that purposely restricted calories in the intermittent fasting group were excluded.

Animal trials

Energy intake and body composition

A total of 36 studies were found. When an alternate-day fasting diet is implemented, overall calorie
restriction and weight reduction occurs in most rodent species, indicating that the restriction on the
fasting day isnt compensated fully on feasting days when food is offered ad libitum (18-34).
Consequently, alternate-day fasting is a widely used model for studying the effects of calorie
restriction in rodent species (15). This however is not a universal finding and numerous studies have
reported no alterations in energy intake and body weight (17,35-39). In general, studies using

Sprague-Dawley and Wistar rats show decreased energy intake and reduced body weights (15,25).
However, C57BL/6 mice maintained on the same alternate-day fasting regimen consume similar
food quantities in a 48-hour time period and maintain body weights similar to that of mice fed ad
libitum (17). The effect of intermittent fasting on body weight thus seems largely dependent on the
animal genotype but could also be affected by the age of initiation, with optimal age varying in the
various rodent strains (40).
Modified alternate-day fasting is one alternative model sometimes used in the intermittent fasting
research. In this model, the animals are not completely fasted every other day, but allowed a small
energy intake of 15-25% of the daily intake consumed by ad libitum fed animals. Modified alternateday fasting could allow for better maintenance of body weight than true alternate-day fasting
protocols (a complete every other day fast) (30,38). The complete compensation and increased
energy intake does not appear to be dependent on the calorie density of the food, since neither a
high-fat or low-fat 85% modified alternate-day fasting diet alters body weight compared to ad
libitum feeding over a four week period (41).
Total body weight however does not reflect alterations in body composition, and there could be
changes in lean mass to fat mass ratio or altered fat distribution which of course would not be
reflected in the animals body weight alone. Alterations in fat distribution were demonstrated in one
study in which mice on both true and modified alternate-day fasting diets showed a redistribution of
adipose tissue from visceral to subcutaneous depots without altering body weight overall (39).

Cardiovascular health
Four rodent studies that examined the effect of alternate-day fasting on cardiovascular disease were
included. In general, rats maintained on an alternate-day fasting regimen lose bodyweight and
display reduced blood pressure and heart rate, and improved insulin sensitivity, compared to rats
fed ad libitum (28,29,42). Reduced blood pressure was also demonstrated in diabetic rats, proposing
that alternate-day fasting can have a preventive effect on the progression of diabetes nephropathy
(32).This data is suggesting that intermittent fasting may reduce the risk of cardiovascular disease.
Furthermore, when myocardial infarction was induced in rats maintained on an alternate-day
fasting diet, reduced infarction size, improved cardiac function, and increased survival was
observed, compared to rats fed ad libitum (24,33,43). More interestingly, the effects on infarction
size, survival rates and cardiac function can be observed even if the dietary intervention is
induced after the ischemic event, by increasing the expression of angiogenic factors and increased
vascularization of the damaged myocardium, proposing a novel non-pharmacological therapy for
subjects with chronic heart failure (43).
A possible contributing factor for the cardio protective effects of intermittent fasting is increased
levels of adiponectin, a hormone that exhibits both anti-athrogenic and insulin sensitizing effects
and has been shown to protect cardiac myocytes against ischemic injury (44,45). Interestingly,
alternate-day fasting demonstrates increased adiponectin levels in numerous rodent studies, even in
the absence of calorie restriction and weight loss (39,46).

Glucose metabolism
A total of seven studies were found. Increased insulin sensitivity, as indicated by decreased fasting
concentrations of glucose and insulin, has been demonstrated in rodents on alternate-day fasts both
with (19,28,33) and without (17) decreased calorie intake. Anson et al. showed that mice on
alternate-day fasting regimen who consume the same amount of food in a 48-hour period as mice
fed ad libitum, decreased glucose and insulin concentrations to a similar degree as did mice on daily
calorie restriction despite maintained energy intake and body weight (17). In another study, as little
as two 24 hour fasts per week, without calorie reduction overall, were sufficient to improve insulin

sensitivity in mice (46). In diabetic rats, alternate-day fasting reduces blood pressure, normalizes
HDL levels, protects against glomerular damage and prevents development of diabetes nephropathy
(32). These findings suggest beneficial effects on glucose metabolism and improved markers
associated with obesity and the metabolic syndrome.

Brain pathology
A total of 17 studies were included. Numerous aspects of intermittent fasting and neuronal health
have been examined in rodent species. Compared to rats fed ad libitum, alternate day fasted rats
showed protection of age-related changes in dendritic spine number and morphology (20). Other
rodent experiments have showed increased neurogenesis in brains of rats maintained on an
alternate-day fasting diet, as evident by increased number of newly generated neural cells in the
hippocampus (21). These results suggest that intermittent fasting could hinder morphological
neuronal changes seen with normal aging and could thus slow down the neuronal aging process.
Other observed effects in mice include increased synaptic plasticity in the hippocampus and
enhancement of learning abilities and other cognitive functions (47).
Intermittent fasting potentially exhibits desirable effects in manifest neuronal diseases. Rats
maintained on alternate-day fasting diets show reduced brain damage and mortality rate in rodent
models of stroke (19,31). After a period of 24 months on alternate-day fasting, a neuroprotective
effect against induced hippocampal excitotoxic damage was observed (25). Epileptic seizures in
animals maintained on an alternate-day fasting diet lead to decreased brain damage (22,26,34).
Beneficial effects have been demonstrated in animal models of neurodegenerative diseases such as
Alzheimers (25,48) and Parkinsons (18) disease. Furthermore, in an animal model of Huntingtons
disease, prolonged survival, reduced disease-associated weight loss and improved motor function
was observed in animals on an alternate-day fasting diet compared to animals fed ad libitum (49).
Interestingly, the protective effect of intermittent fasting against induced excitotoxic brain damage
has been demonstrated in mice despite no reduction in calorie intake or weight loss. Furthermore,
mice on alternate-day fasting diets showed greater resistance to excitotoxic injury than mice on
daily, controlled calorie restriction (17).
When mice with progressive demyelinating disorders of the peripheral nervous system were put on
an alternate-day fasting diet regime, hampered disease progression was observed as indicated by
improved nerve morphology and performance compared to mice fed ad libitum (37). Furthermore,
alternate-day fasting leads to increased functional recovery after experimentally induced spinal cord
injuries in rats, independently if the alternate-day fasting regimen is implemented prior or after the
spinal cord is injured (27,50). If this effect is demonstrated in humans, intermittent fasting could
potentially serve as a non-pharmacological therapeutic alternative in the rehabilitation process in
subjects with spinal cord injuries. The effect in mice was greater with alternate-day fasting
compared to daily calorie restriction, suggesting that increased time span in the fasted state has
additive effects other than those attributed to calorie restriction alone (27).
The beneficial effect does however not appear universal to all neurologic disorders. No desirable
effect was observed in an animal model of amyotrophic lateral sclerosis (ALS), indicating that
intermittent fasting has no beneficial effect on the development of this motor neuron disease (51).

Cell proliferation and cancer

To study the potential anti-carcinogenic effect of intermittent fasting, three different aspects of
tumorgenesis have been studied: circulating markers of insulin-like growth factor-1 (IGF-1), cell
proliferation rates, and direct effect of intermittent fasting on carcinogenesis in animal models.
Seven studies were included.
Subjects with elevated IGF-1 levels have been reported to exhibit increased risk of several cancer
types. Furthermore, high circulating levels of insulin and IGF-1 in combination are often seen in

subjects with obesity, insulin resistance and type 2 diabetes, patient categories that are also more
likely to be affected by cancers (52). Rats on alternate-day fasting diets showed decreased levels of
IGF-1 and proliferation rates of T-cells and prostate cells (30). Cell proliferation rates are
considered a central element in the development of cancers (53). Decreased cell proliferation has
previously been demonstrated with reduced feeding frequency alone, despite matched calorie intake
(54). Mice put on a 85% modified alternate-day fast (eating 15% of ad libitum daily energy intake on
fasting days) reduced IGF-1 levels and decreased proliferation rates of epidermal, prostate, splenic T
and liver cells, despite no weight change (41). In a third study, true but not modified alternate-day
fasting decreased IGF-1 levels in mice. Cell proliferation rates were however reduced in both groups,
even in the absence of weight loss (38).
There is however some conflicting data in regard to intermittent fasting and IGF-1. Two 24 hour
fasts/week without overall calorie restriction showed increased levels of IGF-1 and no effects on
tumor size or survival in rats with prostate cancer (46). One might suspect that two 24 hour fasts
per week would be insufficient to exhibit the anti-carcinogenic effects. However, Anson et al.
displayed increased levels of IGF-1 in mice on alternate-day fasting diets with maintained body
weight compared to controls, in contrast to mice on daily calorie restriction who showed decreases
in bodyweight and decreased IGF-1 (17). The authors suggested a difference in the way intermittent
fasting and calorie restriction influence the growth hormone -IGF-1 axis and insulin signaling
pathways. The relevance of IGF-1 for tumor growth in intermittently fasted animals, with or without
calorie restriction remains thus a subject for further clarification.
Recent research has also examined intermittent fasting and its direct effect on tumor development.
OF1 is a strain of mice that spontaneously develops age related lymphomas at a high rate. In a 16
week trial, none of the mice of this particular strain fed on alternate days developed lymphomas
compared to 33% of mice in the control group fed ad libitum (36). There was no difference in food
intake or body weight between the two groups, suggesting that intermittent fasting has a protective
effect on lymphoma development in this mouse strain, and that the effect was independent of the
total calorie intake. The effect of intermittent fasting on induced hepatocarcinogenesis has also been
examined. When rats were put on a 48 hour fasting regimen once per week, they developed less
preneoplastic lesions compared to rats fed ad libitum over a 48 week period (55). The effects of
shorter, more frequent fasts, such as alternate-day fasting on hepatocarcinogenesis remains a
subject for future research.
Consequently, studies to date indicate that intermittent fasting hampers cell proliferation rates in a
variety of cell types, and that it could potentially protect against direct development of some cancer
types.

Life span
Two studies looked at survival per se. They propose that animals on alternate-day fasting diets
increase life span compared to those fed ad libitum (15,40). The magnitude of life span enhancement
seems to be dependent on animal strain and age of initiation (40). Furthermore, in one study, only
rats on alternate-day fasting diets survived to 30 months of age compared to a mean lifespan of 2224 months for rats fed ad libitum (20).
It is merely speculative if the effect on longevity is secondary to the above described effects such as
decreased body weight, improved insulin sensitivity, improved cardiovascular health, decreased
tumor growth and improved neuronal health, or if intermittent fasting might have some distinctive
effect on the aging process. No study to date has specifically studied the effect of intermittent fasting
without calorie restriction on lifespan, although the effects that have been described are expected to
increase life span. Interestingly, the largest magnitude of life span expansion (25 percent increase in
mean life span) is seen in C57BL/6J mice, the same strain that in many of the studies on alternateday fasting maintain a constant total energy intake and body weight (40).

Other effects
Some other interesting effects than the primary addressed in this review were observed in various
studies. Many strains of laboratory rats develop spontaneous progressive kidney failure with
development of proteinuria and glomerulosclerosis. Rats fed on alternate days showed preserved
kidney function as demonstrated by preserved glomerular filtration rate and renal plasma flow,
compared to rats fed ad libitum (56). Another surprising finding in rats maintained on intermittent
fasting is increased testicular mass and testosterone/estrogen ratio compared to control rats or rats
on a calorie restriction diet (57). Analgesia, which may be attributed to negative modulation of
synaptic transmission in nociceptive neurons in the dorsal horn of the spinal cord, has also been
reported in rats maintained on an alternate-day fasting diet (35). This finding opens up the question
whether intermittent fasting alone or in combination with a pharmacological agent could serve as a
useful new therapeutic approach for treating pain.

Human studies

The Ramadan fast

Fasting is one of the five pillars of Islam. During the holy month of Ramadan, Muslims restrain
from fluid and food intake during daytime for the whole month. Worldwide, there are more than
one billion Muslims, of whom the majority fast annually (58). The holy month of Ramadan could
thus potentially be a good period to study prolonged short term intermittent fasting in humans on a
large scale. A total of 17 studies were found. Conclusions are however very hard to draw from these
studies. Apart from the obvious difficulties with doing randomized controlled trials there is a
number of confounding factors (59,60). Such confounding variables include:
Altered food choices and macronutrient distribution during the fasting month
Dehydration and the difficulties with reliable lab tests
Changes in activity patterns
Reduced sleep due to nighttime eating and socializing
Differences in fasting length and hydration status in different geographical locations and time of year

Furthermore, the studies were generally of poor study design with few participants and lack of
control group. As a result the studies are highly inconclusive with the effects on body weight and
blood lipids with some studies showing unchanged body weight (59,61) while others show weight
loss (62). Therefore, no objective conclusions could be made about this type of short term
intermittent fasting and cardiovascular and metabolic risk factors, and further research of higher
quality is warranted.
In one observational study, young competitive soccer players were sent to a training camp 3 weeks
prior to, and during, the Ramadan fast. The fasting participants were compared to the non-fasting
participants and all food was delivered from the same kitchen, thus eliminating some of the
confounding factors above (60,63). Apart from a small difference in body weight (0,7 kg) that could
be explained by hydration status between the two groups, no differences were observed in blood
glucose levels, hematocrit, cortisol levels, inflammation markers or physical performance. In
another study, fasting healthy men and women were compared to a matched non-fasting group with
regard to inflammation markers and blood lipid status (61). No differences were observed in body
weight, total cholesterol, triglycerides or LDL levels. There was however an increase in HDL levels
and decreased inflammation proposing a beneficial effect in the fasted subjects.
Thus, there are some data suggesting altered health markers during the month of Ramadan, but
more research is needed if any objective conclusions about this type of intermittent fasting and the
factors studied in this review ought to be drawn.

Alternate-day fasting
To date, very few human intervention studies have tried to replicate the reported effects of
alternate-day fasting seen in rodent studies. Only six such studies were found, with somewhat
disappointing study designs (64-69). The sample size in these studies was rather small, ranging
from eight to sixteen participants, and the study period was often very short. Only one trial included
a control group. The results are summarized in Table 2.
In both true alternate-day fasting trials, a decreased body weight was observed (66,67). In modified
alternate-day fasting trials, maintained bodyweight was observed in lean (65,69) but not obese
(64,68) subjects. In obese subjects, a modified 8-10 week alternate-day fasting regimen resulted in
weight loss, reduced blood pressure and heart rate, and improved markers for cardiovascular
health, such as decreased total cholesterol, decreased LDL and triglycerides, increased HDL
concentrations and decreased oxidative stress and systemic inflammation, suggesting that alternateday fasting might be a novel strategy for decreasing body weight and improving cardiovascular
health in the obese population (64,68).
To examine the effects of alternate-day fasting on glucose metabolism, eight healthy men were
maintained on a 20h modified alternate-day fast for two weeks. Despite unaltered body weight and
habitual physical activity, insulin dependent glucose uptake increased, and increased adiponectin
levels were observed (65). In another trial, the insulin sensitizing effect of true alternate-day fasting
was observed through reduced insulin response to a standardized meal in men, but not women
suggesting a potential sex difference in the effect of alternate-day fasting on glucose metabolism
(66). Although not demonstrated in all human studies (68,69), these results indicate that alternateday fasting might mimic the insulin sensitizing effects observed in rodents on alternate-day fasting
diet, and that the effect might be due to increased adiponectin levels.
Sex differences were also observed in another study where healthy men and women were fasted on
alternate days. In this study, HDL levels were increased in women only, and triglycerides were
decreased in men but not women (67). Increased insulin sensitivity was suggested by decreased
insulin levels with unaltered glucose levels. In this study, blood pressure was unaltered, but the
study duration was merely 22 days. In contrast, one trial showed decreased blood pressure and
resting heart rates in subjects on modified alternate-day fasting regimens for 10 weeks, suggesting
that longer intervention periods might be needed for this effect to occur (64). There is, however,
conflicting data from another study that utilized a two week crossover study design and randomized
eight healthy men to a modified alternate-day fasting diet or a standard diet. No differences were
observed in body weight, blood lipids, glucose metabolism or hormone levels, and there was a
decrease in energy expenditure after the 2 week period in the alternate-day fasting group (69). More
controlled studies, with larger sample sizes and longer study durations are thus needed to bring
clarification in this matter.
No human trial has directly examined intermittent fasting and tumor physiology. A single two day
fast increases endogenous GH-production fivefold, reflecting the metabolic adaptation to fasting,
including increased hepatic glucose production, lipolysis and nitrogen conservation (70). However
no significant changes in IGF-1 are seen after a single fast period in human subjects, suggesting that
repeated fasts and longer intervention periods might be necessary to mimic the changes in IGF-1
and altered cancer growth observed in some rat studies. Whether a prolonged alternate-day fasting
regimen can alter IGF-1 levels in humans remains an area for future research. Furthermore, no
human trials to date have examined the effects of intermittent fasting on neuronal health or life
span.

Mechanisms of calorie restriction and intermittent fasting

The exact mechanism by which calorie restriction and intermittent fasting exhibits its effects on
various organ systems remains unknown. The main hypothesis includes a stress preconditioning
response mechanism, in which it is believed that periods of nutrient deprivation displays a
beneficial mild stress that results in molecular adaptive changes in various tissues, which increases
the organisms resistance to bigger stressors such as excitotoxic and oxidative injury, including
ischemia (33,71). Alternating periods of anabolism and catabolism during intermittent fasting might
further increase the cellular stress resistance. Other displayed effects are increased production of
neutrophilic factors and antioxidant enzymes, ketone body formation and altered metabolism
enzyme production (5).

Potential adverse effects from fasting

Blood glucose levels, mood and cognition

A variety of questions often arises when discussing intermittent fasting and human health. It is
often believed that blood sugar levels will fall to pathological levels if prolonged fasts are
implemented. A characteristic decline in mood and energy levels before lunch among humans is
often attributed to a drop in blood sugar. However when actually testing blood sugar levels in
healthy subjects prone to this phenomena, no actual decline in blood sugar to pathologic levels was
seen during a 24 hour fast (72). In healthy human subjects, a 24 hour fast decreases liver glycogen
stores no more than 57% and in absence of vigorous exercise does not lead to muscle glycogen
consumption, suggesting that liver glycogen stores are sufficient after a 24 hour fast to keep blood
glucose levels within normal range (73). Furthermore, a double-blind, placebo-controlled study of
two days of calorie deprivation showed no adverse effect on cognitive performance, activity, sleep,
and mood, when the subjects were unaware of the calorie content of the treatments (74).

Hunger
The homeostasis of body weight regulation and hunger signaling is composed of complex circuits of
both central signals including orexin, neuropeptide Y, melanin concentrating hormone and alphamelanocyte, and peripheral signals from the gut and adipose tissue, such as ghrelin, peptide YY and
leptin (75). The interplay between these and other endocrine signaling systems and its effect on
body weight regulation and subjective feelings of hunger and satiety remains largely unknown. The
hunger response however seems to be highly adaptive in different meal patterns. Ghrelin, a gut
derived hormone, is considered a meal-initiation signal. It increases during fasting and usually
peaks in concentration before an anticipated meal, paired with increased feelings of hunger, and
decreases after feeding. Interestingly, the rise in ghrelin is independent of meal timing as
demonstrated by similar peaks before an anticipated meal in various meal frequencies, thus
suggesting that subjective feelings of hunger and energy intake is highly dependent on the
individuals preferred meal pattern (76).
Increases in subjective feelings of hunger might be the single most important factor to consider
when discussing the applicability of intermittent fasting as a therapeutic or preventive intervention
in human subjects. In obese patients, a 14 day total fast lead to strikingly decreased body weights
and decreased blood pressure, without causing increased hunger sensations. Thus a hunger
suppressing effect of prolonged fasting was demonstrated (77). This anorexic effect might be
attributed to the evolutionary purpose of seeking for nutrients in absence of food. The experiment,
dating back to 1962, was effective and well tolerated.
Only one study has directly examined the feelings of hunger and fullness in non-obese subjects on
an intermittent fasting diet, by using a 100 mm visual analog scale (67). The subjects were fasted on
alternate days and reported an increased feeling of hunger from 37 to 56 mm and decrease in feeling
of fullness from 43 to 23 mm when the dietary intervention was initiated. The magnitude of hunger

did however not change during the intervention period as repeated measurements were taken, and
feelings of fullness actually increased some over time. The duration of this study was only 22 days
and it is still purely speculative whether and adaptation to the new meal pattern would occur in a
longer time span. In contrast, modified alternate-day fasting in obese asthmatic patients did not
significantly increase the subjective perception of hunger from baseline during the eight week long
intervention period (68).
Whether repeated bouts of short term fasting can alter hunger hormone signaling or demonstrate
the same anorexic effect as the long term fast described above is highly speculative and an
interesting area for future research.

Decreased metabolic rate

It is commonly believed that multiple small meals increase metabolism and lead to increased overall
energy expenditure. Following every meal there is an increase in expenditure due to the processing
of the nutrients, commonly referred to Thermic Effect of Food (TEF) (78). A common belief
therefore is that increased meal frequency leads to increased TEF and increased overall energy
expenditure with multiple meals, and that intermittent fasting accordingly would decrease
metabolic rate and lead to increased fat accumulation and possibly obesity. According to current
research though, TEF is proportional to the calorie content and vary with macronutrient
composition (with the highest increase in energy expenditure observed with a high protein diet) and
not meal frequency per se, as demonstrated by the equal TEF in different meal patterns under isocaloric conditions (79,80). Furthermore, one study examined alterations in resting metabolic rate in
human subjects on alternate-day fasting diets, and found no changes after a 22 day period (67).
According to these findings, any potential decreases in metabolic rate would be due to decreased
total calorie intake and not fasting per se.

Increased stress
Increased levels of both ACTH and corticosteroids can be noted in rodents maintained on alternateday fasting diets compared with rats fed ad libitum (28,29,42). Apart from the obvious notion that
cortisol is one of the major hormones responsible for glucose utilization during fasting, the question
arises whether the increased stress in any way could be harmful to the human organism. The
molecular stress response in intermittently fasted subjects seems markedly different from the one
associated with uncontrolled stress. In fasted rodents there is actually a down regulation of
glucocorticoid receptors in the brain, with maintained expression of mineralocorticoid receptors,
suggesting that fasting might alter the brains responsiveness to glucocorticoids (81). In contrast, in
uncontrolled stress, down regulation of the mineral corticoid receptor has been noted. Furthermore,
deleterious stress responses are associated with a decrease in the expression of brain-derived
neurotrophic factor (BDNF), a response quite the opposite of calorie restriction and intermittent
fasting, where increased concentrations of BDNF have been observed in numerous studies (4). In
conclusion, the controlled stress response from intermittent fasting seems fundamentally different
from the one by uncontrolled physiological and psychological stress. Conversely, In line with the
mechanisms described above, the increased stress might be one of the necessary factors for
initiating molecular resistance for larger stressors, and thus promote some of the beneficial effects
of intermittent fasting.

Loss of muscle mass

One potential serious side effect of intermittent fasting would be loss of muscle mass. Theoretically,
food deprivation would result in depleted hepatic glycogen stores, leading to increased proteolysis
and flux of amino acids from skeletal muscle for hepatic de novo gluconeogenesis, to maintain healthy

blood glucose concentrations. As discussed previously though, a 24 hour short term fast is
insufficient in duration to deplete liver glycogen stores in healthy subjects (73). Up to 40 hours of
total fasting does not stimulate catabolic processes and lead to skeletal muscle atrophy (82).
Modified alternate-day fasting and loss of lean body mass was investigated in only one study in the
systematic search. No loss of fat free mass in the absence of weight loss was observed compared to a
control group fed a standardized diet (69). Furthermore, an increase in ketone body concentrations
has been observed in subjects on alternate-day fasting diets in both human and animal studies
(17,68). Ketone bodies spare skeletal muscle from breakdown by providing non-glucose energy
substrate for various tissues, of which the brain is the most important, and thus decrease the need
for protein-derived substrates for gluconeogenetic conversion to maintain glucose homeostasis (83).
Available data thus suggests that short term fasting does not deplete hepatic glycogen stores to the
extent that markedly increased proteolysis and gluconeogenesis becomes necessary to maintain
healthy glucose concentrations. Still this notion needs to be clarified in future research of longer
duration.

Conclusions

Alternate day fasting as a model for calorie

restriction
Intermittent fasting in the form of alternate day fasting in many instances reduces overall energy
intake, with no obvious adverse effects, and thus becomes a model of calorie restriction in both
human and animal subjects. Secondary to reduced energy intake and weight loss, effects such as
reduced risk factors for cardiovascular disease, and improved glucose metabolism have been
demonstrated in both animal and human subjects on true and modified alternate-day fasting diets.
In rats, protection against ischemic injury and improved survival has been demonstrated in both
myocardial and cerebral ischemic events. Other beneficial effects, such as slowing the neuronal
aging process and increasing cognitive functions and memory, have been observed. In line with
animal studies on daily calorie restriction, alternate-day calorie restriction has shown beneficial
effects in neuronal disorders such as stroke, epilepsy and neurodegenerative disorders, including
Alzheimers, Parkinsons and Huntingtons disease. Additionally, calorie restriction can reduce
cancer risk and increase life span in rodent models on alternate-day fasting diets.

Intermittent fasting and health

absence of calorie restriction

in

the

Some effects occur even if the subject maintains body weight, suggesting that the reduced meal
frequency or prolonged time in the fasted state might have some additional effects regardless of
overall calorie restriction and weight loss. In humans, modified alternate-day fasting diets might be
easier to adhere to and they seemingly lead to less pronounced weight loss than true alternate-day
fasting. Without causing weight loss, effects such as improved fasting insulin have been
demonstrated in both animals and humans. In line with these findings, adiponectin increases in rats
and humans on both true and modified alternate-day fasting diets in the absence of calorie
restriction. Additionally, in mice, fat redistribution from visceral to subcutaneous stores has been
observed despite unaltered overall body weight. If this effect proves to be true in human subjects it
could propose reduced disease risk despite unaltered body weight.
Animal data further indicate some beneficial effects of intermittent fasting diets even without
calorie restriction. Neuronal health improvements such as resistance to excitotoxic injury have been

observed. Resistance to oxidative stress could be beneficial in the pathogenesis of epilepsy and
various neurodegenerative diseases such as Alzheimers disease. Alternate-day fasting in animals
also leads to improved recovery after induced spinal cord injuries and progressive demyelinating
disease of the peripheral nervous system, in the absence of calorie restriction. Furthermore, in
animal studies, changes associated with retareded tumorgenesis, such as decreased cell proliferation
rates in various cell lines and decreased incidence of lymphoma, have been observed. Whether these
observations are valid in human subjects as well remains an interesting area for future research.
Future research is warranted to test whether the health promoting effects described in animal
studies have some validity in humans. We are in the very infancy of research on intermittent fasting
in human subjects and future studies with larger sample sizes, longer durations and of better study
design must be completed before any definite conclusions can be made regarding intermittent
fasting and human health and the applicability to modern lifestyle.

Acknowledgement
My sincere gratitude to Staffan Lindeberg and Bengt Zller for helping me set up the systematic
search, for all the intellectually stimulating discussions and for the guidance in writing this review.

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Table 1: Used search terms

The complete search term used was: (Hunger/physiology[mesh] OR Cholesterol/metabolism[mesh]
OR Blood Pressure/physiology[mesh] OR Body Composition/physiology[mesh] OR Blood
Glucose/metabolism[mesh] OR Energy Metabolism/physiology[mesh] OR Cardiovascular
Diseases/prevention[mesh]
OR
Diabetes
Mellitus,
Type
2/prevention[mesh]
OR
Neoplasms/prevention[mesh] OR Caloric restriction[mesh] OR Caloric restriction/methods[mesh]
OR Fasting[mesh] OR Fasting/physiology[mesh] OR Fasting/blood[mesh] OR Feeding
behavior[mesh] OR Obesity[mesh] OR Energy intake[mesh] OR diet/methods[mesh] OR
eating/physiology[mesh] OR Ghrelin/blood[mesh] OR Ghrelin/metabolism[mesh] OR
Glucagon/blood[mesh] OR Glucagon/metabolism[mesh] OR Insulin/blood[mesh] OR
Insulin/metabolism[mesh] OR Insulin Resistance/physiology[mesh] OR Leptin/blood[mesh] OR
Leptin/metabolism[mesh]) AND (Short term fasting OR Short term fast OR Intermittent
fasting OR Intermittent fast OR Periodic fasting OR Periodic fast OR Alternate-day fasting
OR Alternate-day fast OR Alternate day modified fasting OR Alternate day modified fast OR
Every other day feeding OR Reduced meal frequency OR Nibbling gorging OR Hormesis OR
Omitting breakfast OR Omit breakfast OR Skipping breakfast OR ramadan OR fasting
refeeding OR Alternate day caloric restriction).
Table 2: Alternate day fasting and body weight, glucose metabolism and cardiovascular health in humans
Reference

Subjects (n)

Protocol

Trial leng

Soeters et al, 2009 (69)

8, non-obese

20 h mod ADF

2wk cros

Varady et al, 2009 (64)

16, overweight

75% mod ADF

10wk

Johnson et al, 2007 (68)

10, overweight, asthmatic

80% mod ADF

8wk

Heilbronn et al, 2005a (67)

16, non-obese

ADF

22d

Heilbronn et al, 2005b (66)

16, non-obese

ADF

22d

Halberg et al, 2005 (65)

8, non-obese

20 h mod ADF

15d

Abbreviations: ADF, alternate-day fasting; mod ADF, modified alternate day fasting; BP, blood pressure; HR,
heart rate; TCL, total cholesterol; LDL, low-density lipoprotein; HDL, high-density lipoprotein; TG,
triglyceride. -, unaltered; , increase; , decrease.
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